Platinum-(II)-diamine complex, method for the preparation of this compound, preparation with an anti-tumour action which contains this compound and also shaped preparations with an anti-tumour action.
The invention relates to a platinum-(II)-diamine complex and also to a method for the preparation of this compound, to a preparation with an anti-tumour action which contains this compound and also to shaped preparations with an anti-tumour action.
About twenty years ago the American biochemist B. Rosenberg discovered that cis-diamine-dichloroplatinum (cis-platinum) exhibits a very strong anti-tumour activity; B. Rosenberg, L. van Camp, J. Trosko and V. H. Mansour, Nature 222, (1969) pages 385-386. In the meantime this compound, in combination with other anti-tumour agents, has found important applications in the treatment of tumours, in particular of the ovary and testes. Cis-platinum has, however, a number of highly undesirable side effects. It causes severe nausea in the patient, in combination with vomiting. In addition, it displays kidney, bone marrow and neurotoxicity and can cause damage to the hearing. Reference is made here, for example, to the article by D. Th. Sleijfer, S. Meijer and M. H. Mulder, Cis-platin: a review of clinical applications and renal toxicity. Pharm. Weekbl. [Sci.] 1985; 7: pages 237-244. Since the start of the 1970s, a great deal of research has also been carried out world-wide on the mechanism of action of cis-platinum and on the development of analogues with a higher anti-tumour activity and/or activity against tumours not susceptible to date, analogues with reduced toxic side effects and/or analogues with improved physical and pharmacological properties.
Numerous platinum-diamine complexes are known from the literature. However, there is still a great need for new anti-tumour agents, specifically for compounds with activity against tumours which are resistant or have developed resistance to cis-platinum.
Reference is made here, for example, to two recent review articles and to the literature references mentioned therein; E. W. Stern, The Search for New Platinum Antitumor Agents: Progress, Problems and Prospects, in Platinum and other Metal Coordination Compounds in Cancer Chemotherapy, Edited by Marino Nicolini, Martinus Nijhoff Publishing, Boston, Dordrecht, Lancaster, ISBN 0-89838-358-7, 1988, pages 519-526; H. A. Meinema, Platinaverbindingen ter bestrijding van kanker: synthese, eigenschappen en structuuractiviteitsrelaties (Platinum compounds for combating cancer: synthesis, characteristics and structure-activity relationships) Pharm. Weekbl., 123 (1988) pages 549-552.
Diamine-platinum complexes are described in Dutch Patent Application No. 79.04740 which are shown in FIG. 1 of the drawing where R.sub.1 and R.sub.2 independently of one another represent a hydrogen atom or a substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group, while R.sub.1 and R.sub.2 together with the carbon atom to which they are bonded can be a substituted or unsubstituted cycloalkyl group, R.sub.3 and R.sub.4 independently of one another represent a hydrogen or a substituted or unsubstituted alkyl, aryl or aralkyl group and X represents an anionic group.
Diamine-platinum complexes are known from Dutch Patent Application 82.04067 as shown in FIG. 1 of the drawing wherein R.sub.1 and R.sub.2 both represent an ethyl group or, together with the carbon atom to which they are bonded, a phenyl group (it is pointed out here that the examples indicate that it is not a phenyl group but a cycloalkyl group which is meant), R.sub.3 and R.sub.4 both represent a hydrogen atom and each X represents a chloroacetate or nitrate group, or two symbols X together represent a malonate group, an ethylmalonate group, a hydroxymalonate group, a carboxyphthalate group, a cyclobutane-1,1-dicarboxylate group or an oxylate group, or a sodium salt of one of these groups.
Extensive research carried out by the National Cancer Institute, Bethesda, U.S.A. and the European Organization for Research on the Treatment of Cancer, Brussels, Belgium, has shown that these compounds exhibit a high therapeutic activity against cancer. In comparison with other platinum complexes for combating cancer which are known and are used in practice, these complexes have a lower kidney toxicity.
Platinum complexes with an anti-tumour action are known from Dutch Patent Application 80.00032, now patent 181,434, which has the formula shown in Figure of the drawings, wherein R.sub.1 and R.sub.2 independently of one another represent a hydrogen atom or a substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group, while R.sub.1 and R.sub.2, together with the carbon atom to which they are bonded, can form a substituted or unsubstituted cycloalkyl group, R.sub.3 and R.sub.4 independently of one another represent a hydrogen atom or a substituted or unsubstituted alkyl or aralkyl group and X and Y represent identical or different anionic groups. These compounds also exhibit an action against a number of types of cancer and a reduced kidney toxicity.